PROJECT SUMMARY/ABSTRACT Multiple sclerosis (MS) is a common neurologic disease that can result in significant restriction in activity and participation. MS is caused by intermittent inflammation causing demyelination and axonal damage. The promotion of remyelination is a promising therapeutic strategy to overcome and prevent MS disability by improving the conduction velocity of action potentials and providing neuroprotective insulation for the axon. Effective remyelination will likely require a multimodal approach, including rehabilitative and pharmacologic therapies, to stimulate remyelination along neural pathways. In animal models of MS, aerobic exercise can promote remyelination alone or synergistically with pharmacotherapy. However, it is currently uncertain how to measure remyelination in people with MS and this lack of a reproducible and reliable measure of myelin status is a major obstacle to the development of remyelination therapies. Prior to the successful development of large-scale multimodal clinical trials, there is a crucial need to 1) determine the optimal outcomes to assess the extent of remyelination, and 2) demonstrate the feasibility and study design of a rehabilitative aerobic exercise intervention. The central hypotheses of this study are that 1) spinal cord demyelination in MS, as measured by prolongation of somatosensory evoked potential (SSEP) latency, is associated with reduced function, activity and participation in people with MS, and 2) aerobic stationary cycling is a safe and feasible rehabilitative intervention in people with MS to improve mobility. Besides addressing these hypotheses, we will gather preliminary data on the effects of aerobic exercise on SSEP latencies, walking speed, and other measures of activity and participation. SSEPs are an ideal objective measure as they are inexpensive, reproducible, commercially available, and provide a functional measure reflecting myelination in the spinal cord. This proposed study will explore the association between myelination, as assessed by SSEPs, and a panel of outcome measures of body structure, function, activity and participation, to determine optimal clinical outcomes to monitor remyelination. This study will also determine the safety and feasibility of a 24-week aerobic stationary cycling intervention as compared to an MS symptom education control intervention in a randomized, single-blind, parallel clinical trial in people with MS. An experimental aim will explore if aerobic stationary cycling is associated with improvements in mobility and remyelination of the spinal cord, as measured by SSEP. The goal of this study is to lay the ground work needed to design and implement a future, R01-funded, multimodal, randomized clinical trial of aerobic stationary cycling and pharmacotherapy to stimulate remyelination in people with MS.